DESCRIPTION: SPARC is a matricellular protein that functions through disruption of cell-matrix interactions. As such, it provides a structurally characterized prototype for this newly defined class of regulatory macromolecules. The expression of SPARC in remodeling tissues, as a consequence of normal development or response to injury, coupled with its multiple regulatory effect on cultured endothelial cells, has been consistent with our proposal that SPARC subserves a fundamental role in vascular morphogenesis and cellular differentiation. The process of blood vessel growth encompasses several discrete but often coincident endpoints which endothelial cells must achieve for the genesis of an intact vascular bed. At which of these points does SPARC function? From recent studies on cultured endothelial cells, this laboratory has shown that SPARC acts initially as a counteradhesive protein through a pathway dependent on tyrosine phosphorylation, and distally as an inhibitor of the cell cycle. Other levels of regulation that are potentially important are a) abrogation of the mitogenic effect of vascular endothelial growth factor (VEGF) on the endothelial cell cycle through a direct interaction with SPARC , and b) proteolysis of SPARC into bioactive peptides. They propose that SPARC alters the kinetics of the interrelationship among endothelial cells, mitogens, and extracellular matrix, and thus predisposes the endothelium toward an activated state requisite for vascular growth. This renewal application addresses the structural and mechanistic correlates of SPARC function at specific stages of vascular morphogenesis in vivo and in vitro. The proposed experiments should result in a more precise understanding of how vessels grow in the context of signals mediated by the matricellular protein SPARC , a dynamic resident of the extracellular space.